Although behavioral effects of thyroid disorders have long been recognized, until recently there has been little clear evidence of a neuronal basis for these actions. It has now been shown that thyroid hormones are taken up and metabolized in the synaptosmal fraction of brain and that changes in thyroid state alter neurotransmitter synthesis and turnover and the status of several types of neurotransmitter receptors. In addition, clinicians have used thyroid hormones to potentiate the therapeutic effects of antidepressant drugs, which also effect synaptic processes. These findings suggst a functional role of thyroid hormones at the synapse. With tehse considerations in mind, we conducted a pilot study of the effects of thyroid hormones on the uptake of a variety of neurotransmitters. We observed that in fresh homogenates of rat cerebral cortex T3 and T4 inhibited the nuronal uptake of GABA and 5-HT but not of NE, DA, aspartic asid or choline. We are submitting a proposal to continue and expand this work on the effects of thyroid hormones on neurotransmitter uptake and other synaptic processes. The major aims are to further characterize the effects of thyroid hormones on GABA and 5-HT uptake in homogenates and purified synaptosomes from cerebral cortex and other brain regions, to investigate the effects of chronic hyperthyroidism and hypothyroidism on neurotransmitter uptake, to examine the effects of thyroid hormones and thyroid status on GABA and 5-HT receptors. We also plan to investigate the interactive effects at the synaptic level of thyroid hormones and antidepressant drugs. Because of similarities between some of the structural and physiological properties of thyroid hormones and aromatic acid neurotransmitters, we will investigate whether rT3 is taken up by synaptosomes (like T4 and T3), whether thyroid hormones are released in the manner of proven neurotransmitters, and whether thyroid hormones bind to receptors on synaptosomal membranes.